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With pyridine; thionyl chloride In 1,2-dichloro-ethane |
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With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 1h; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 16h; |
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With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 40℃; for 1h; |
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With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h; |
4
SOCl2 (1.60 mL, 21.6 mmol) and a few drops of dry DMF were added to a solution of 4-bromobutyrric acid (3.00 g, 18.0 mmol) in dry CH2Cl2 (40 mL) , stirred under N2 at r.t. The stirring was continued for 3 h at r.t. The solution of the acyl chloride so obtained was slowly added to a stirred solution of salycilic aldehyde (1.73 mL, 14.4 mmol) and dry Pyridine (2.20 mL, 27.0 mmol) in dry CH2Cl2 (40 mL) , kept under N2, at 0 0C. The reaction was allowed to reach r.t. and was completed after 2 h. The mixture was washed with HCl 2M (3 x 30 mL) . The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc 90/10 v/v) to give the title compound as pale yellow oil (3.54g) . Yield 80 %. TLC: Rf = 0.67 PE/EtOAc 80/20 v/v1H-NMR (CDCl3) δ 2.34-2.36 (2H, m) , 2.87-2.92 (2H, m) , 3.55-3.60 (2H, m) , 7.18 (IH, d, Arom ), 7.43 (IH, t, Arom ), 7.66 (IH, t, Arom ), 7.88 (IH, d, Arom ), 10.1 (IH, s br) . 13C-NMR (CDCl3) δ 27.4, 32.3, 32.5, 123.5, 126.5, 132.0, 134.8, 151.0, 171.0, 188.9. MS (CI) m/z 271/273 (M+l)+. |
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With thionyl chloride at 20℃; for 1h; |
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With oxalyl dichloride In dichloromethane at 20℃; for 1.75h; |
1
Preparation of 4-bromobutyryl chlorideTo a solution of 4-bromobutyric acid (2.00 g, 12.0 mmol, 1.2 eq.) in DCM (40 mL) was added oxalyl chloride (2 M in dichloroethane, 36 mL, 18 mmol, 1.8 eq.) and catalytic DMF (20 μL). The mixture was stirred at room temperature for 1.75 hours and the solvent was removed via rotary evaporation to provide 4- bromobutyryl chloride (high vacuum was not used to dry the product due to its potential volatility). The crude material was used immediately in the next step without further purification. |
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With oxalyl dichloride In dichloromethane at 20℃; for 4h; |
4
Preparation of 2-(4-bromobutanamido)-7V-(4-fluorobenzyl)-4-methylthiazole-5- carboxamideTo a solution of 4-bromobutanoic acid (4.40 g, 26.0 mmol) in anhydrous dichloromethane (100 mL) was added two drops of λ/,iV'-dimethylformamide, followed by the addition of oxalyl chloride (4.99 g, 39.0 mmol) dropwise. The reaction was stirred at ambient temperature for 4 hours. The solvent was removed in vacuo to afford 4- bromobutanoyl chloride (4.87 g, 26.0 mmol) as a yellow oil, which was used in the next step without further purification. |
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With thionyl chloride In dichloromethane at 20℃; for 2h; |
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With thionyl chloride for 3h; Reflux; |
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With oxalyl dichloride In dichloromethane at 20℃; for 5h; |
41.1
Step 1 A solution of 4-bromobutanoic acid (25.0 g, 150 mmol), DMF (5 drops) and oxalyl chloride (17.0 mL, 195.0 mmol) in dichloromethane (250 mL) was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, dichloromethane (200 mL) and ethanol (9.0 mL, 170 mmol) were added to the residue, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and the organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0 - 5% ethyl acetate/hexane) to give ethyl 4-bromobutanoate as a colorless oil (24.5 g, 84%). |
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With thionyl chloride In chloroform at 20℃; for 24h; |
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With oxalyl dichloride In dichloromethane at 25℃; Inert atmosphere; |
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With thionyl chloride for 0.5h; Cooling with ice; |
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With oxalyl dichloride at 20℃; for 0.75h; Inert atmosphere; |
General procedure for the synthesis of ?-bromo-N-(4-bromophenyl)alkanamides (10a-e)
General procedure: The appropriate ω-bromoalkanoic acid (1 mmol) was suspended in oxalyl chloride (ca. 2 mL), stirred at ambient temperature for 45 min, and the excess oxalyl chloride evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), cooled to -78 °C, and treated dropwise with a solution of 4-bromoaniline (1.1 mmol) and Et3N (1.1 mmol) in CH2Cl2 (11 mL). The mixture was warmed to ambient temperature, stirred for 1 h, and CH2Cl2 (50 mL) was added. The solution was washed with H2O (50 mL), 1 M aq. HCl (50 mL), sat. aq. Na2CO3 (50 mL), brine (50 mL), dried (MgSO4), and the solvent evaporated under reduced pressure to give crude amides 10a-10e. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; |
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With thionyl chloride at 75℃; Inert atmosphere; |
General procedure for preparation of bromoacyl esters (8c and 8d) through acid chlorides (7c, 7d:
5-bromovaleric acid (1 equiv) or 4-bromobutyric acid (1 equiv) was dissolved in thionyl chloride (4.5 equiv). The reaction mixture was then heated (75 C, oil bath) under a nitrogen atmosphere overnight. The excess thionyl chloride was removed by adding dichloromethane (25 mL) followed by rotary evaporation under aspirator vacuum. The addition of the dichloromethane and rotary evaporation was repeated (3 ) which yielded the crude acid chloride as an oil. The 5-bromobutyryl chloride 7c or the 4- bromovaleryl chloride 7d were used without further purification in the next step. Benzoin (1 equiv) was dissolved in pyridine (12 mL) followed by cooling the solution to 0 C (ice water bath). The acid chloride 7c, 7d (1 equiv) was then added dropwise to the stirred solution while cooling and stirring. The reaction flask was capped, and after 30 min, the cooling bath was removed. The reaction mixture was then stirred (4 h) at room temperature while monitoring by TLC. After the starting materials were consumed, the reaction mixture was then dissolved in dichloromethane (300 mL) and washed with 5% aqueous HCl (5 120 mL). The organic layer was then separated and dried over anhydrous sodium sulfate. Flash chromatography on silica gel (hexane/ethyl acetate, 6:1) afforded esters 8c (70%) and 8d (23%) as oils |
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With thionyl chloride; N,N-dimethyl-formamide In dichloromethane |
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With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; |
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With thionyl chloride |
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With phosphorus trichloride |
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With thionyl chloride at 20℃; Further stages; |
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With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; |
1.1. 3-(3-bromopropanamido)benzoic acid (3a)
General procedure: In ice bath, 3-bromopropanoic acid (1a, 1.53 g,10 mmol) was dissolved in dichloromethane (30 ml), oxalyl chloride (1.71 ml, 20 mmol) and one drop of dimethylformamide were added. The solution was stirred for 4 h at room temperature. The solvent and excess oxalyl chloride was evaporated. Then, the produced 3-bromopropanoyl chloride was dissolved in 10 ml THF and dropped in the mixture of 3-aminobenzoic acid (2a,1.37 g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol) in THF. After stirred for 8 h, the solvent was removed and the mixture was acidified with 1M HCl. The final product was purified by recrystallization with ethanol. Yield 66%, mp: 210-211 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.93(s, 1H), 10.23 (s, 1H), 8.24 (t, J =1.6 Hz,1H), 7.81 (dt, J = 8.0 Hz, 1.6Hz, 1H), 7.63 (dt, J = 8.0 Hz, 1.6Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H),3.74 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H). |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 4 - 25℃; |
1.4 General procedure for the preparation of compounds (2d-2o)
General procedure: To a solution ofbromocarboxylicacids (0.2mol) in dichloromethane (200 mL) was addedoxalylchloride (0.4mol) at 4oC.N,N-dimethylformamide(2 mL) was then added cautiously, and the reaction was stirred for 4 h at 25oC.The solvent was removed by distillation under vacuum at 30-40oC.This concentrate was taken directly into the next stage. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Inert atmosphere; |
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With oxalyl dichloride In tetrahydrofuran at 20℃; for 1h; |
Intermediate 19D.; 4-Bromo-N-[6-(3,5-dimethyl-pyrazol-1 -yl)-2-(5-methyl-furan-2- yl)-pyrimidin-4-yl]-butyramide EPO To 10 mL THF were added 3.Og (18mmol, 2eq) 4-bromobutyric acid, 2.5g (2.2eq) oxalyl chloride, followed by a few drops of DMF. The reaction mixture was stirred at r.t. for 1 hour. Solvent was removed by nitrogen flow and the residue was resuspended in 10 mL dichloromethane followed by of Intermediate 19C and 0.9 mL pyridine. The reaction mixture was stirred at r.t. for 2 hours. The reaction was quenched with 5OmL saturated sodium bicarbonate, extracted twice with 5OmL dichloromethane, the organic layers were combined, dried under sodium sulfate and concentrated to give Intermediate 19D. Intermediate 19D was used in the next step without further purification. |
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With oxalyl dichloride at 20℃; for 4h; Inert atmosphere; |
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With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; |
39
[0393] To a solution of 4-bromobutanoic acid (3.4 g, 21 mmol) in dichloromethane (30 mL) was added thionyl chloride (3.68 g, 30.9 mmol) and dimethyl formamide (75 mg, 1.0 mmol). The mixture was stirred for at 0°C 1 hour. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (10 mL). The resulting solution was added to a mixture of 3-04-2 and diisopropylethylamine (3.99 g, 30.9 mmol) in dichloromethane (30 mL). The mixture was stirred at 20°C for 30 min then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 - 3 : 1) to afford compound 3-04-3 (4.8 g, 87.47% yield) as a white solid. |
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With thionyl chloride for 2h; Reflux; |
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With thionyl chloride In N,N-dimethyl-formamide at 50℃; for 1h; |
To a solution of 1-bromobutyric acid (16.7 parts by weight) and DMF (100 parts by weight), thionyl chloride (11.9 parts by weight) was added dropwise,The mixture was reacted at 50 ° C. for 1 hour, followed by addition of 3-isopropoxypropylamine (11.7 parts by weight), and reacted at 50 ° C. for 3 hours. After the reaction, unreacted thionyl chloride was distilled off. Subsequently, o-mercaptophenol (12.6 parts by weight) and potassium carbonate (30 parts by weight) were added, and the reaction was carried out at 50 ° C. for 5 hours. After the reaction, liquid separation was performed with ethyl acetate and 1N aqueous hydrochloric acid, and the organic layer was concentrated and purified by silica gel column chromatography to obtain compound A-124B. |
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With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; |
11; 21 Synthesis of 11-1
To a solution of 4-bromobutyric acid (0.97 mmol, 161mg) in CH2C12 (3 mL) and DMF (0.01 mL) was added oxalyl chloride (3 eq, 2.91 mmol, 370 mg, 0. 25 mL) at RT. The mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. The residual liquid/solid (slightly yellow) was dissolved in 5 mL of CH2C12 and was added a solution of 8-2 (410 mg, 0.48 mmol), triethylamine (0.4 mL) and DMAP (2 mg) in CH2C12 (20 mL) at RT in 2 min. After addition, the resulting mixture was stirred at RT for 2.5 h. TLC (Hexane/ethyl acetate = 9: 1) showed two major spots. The reaction mixture was then concentrated at RT under reduced pressure. The residue was used for the next reaction without any purification. |
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With thionyl chloride for 2h; Reflux; Inert atmosphere; |
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With thionyl chloride at 75℃; for 2h; Sealed tube; Inert atmosphere; |
4.2. General procedure for synthesis of 3a-d
General procedure: The reaction vessel was capped and heated to 75 C for 2 h and thesolvent was removed by rotary evaporation. To the crude acidchloride was added isobutanol (10 mL), and the resulting mixturewas allowed to sit at 25 C for 12 h. The solvent was removed byrotary evaporation to provide the crude product which was sufficientlypure to carry forward. |
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With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 1h; |
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